The purpose of this grant is to support Dr. John Karro in refocusing his research from computer science into the fields of bioinformatics and genome analysis. Dr. Karro wishes to give up his position as an assistant professor at Oberlin College, with the long-term goal of obtaining a tenure-track position at a major research university with an established bioinformatics program. Here we propose a didactic plan of courses, training and research with Webb Miller and his colleagues at Pennsylvania State University, designed to provide Dr. Karro with the needed biological background and experience to achieve this goal. In recent years we have seen a dramatic increase in the potential for understanding the structure, function and evolution of vertebrate genomes by means of comparative analysis. With data continually emerging from newly sequenced genomes, the potential for comparative analyses to contribute to our understanding of genomics is unlimited. Unfortunately, the need for new software tools to perform these analyses has outpaced our ability to write such tools. The established computational techniques for comparing small fragments fall short when applied to whole genomes. The run-time and memory requirements of these algorithms make their use infeasible, and they are unable to account for many types of evolutionary events that can be found in larger genomic sequences (e.g., inversion or duplication). Few tools are able to accurately align three or more genome sequences simultaneously, and good methods are needed for storing the results of whole-genome alignments in ways that allow researchers to query them in an efficient manner. This problem provides a perfect entry point for Dr. Karro into bioinformatics: as an established researcher in algorithmic theory he will quickly be able to contribute, while at the same time use the experience to obtain the necessary background and insight to the issues motivating research in bioinformatics.